Early work in Dr. Lyden's laboratory resulted in several fundamental discoveries that involve the role of bone marrow-derived stem and progenitor cells in tumor vasculogenesis and in metastasis. His lab has shown the first evidence of genetic regulation in vasculogenesis with the discovery of one family of genes called Id1-4 in early blood vessel development in embryogenesis and in tumorigenesis (Nature 1999, 401:670-677). Dr. Lyden and colleagues subsequently identified two bone marrow-derived cell types, endothelial progenitor cells (EPCs) and hematopoietic progenitor cells (HPCs) of myeloid origin that both participate in the formation of new blood vessels in the primary tumor that occurred by vasculogenesis as opposed to angiogenesis (Nature Medicine 2001, 9:702-712). Building upon this work, Dr. Lyden's laboratory recently showed that Id1 also plays a critical role in suppressing the anti-tumor immune response during tumor progression and metastasis (Nature Communications 2015 Apr 29;6:6840). More specifically, his group showed that upregulation of Id1 in response to tumor-derived factors such as TGFβ is responsible for the switch from dendritic cell differentiation to myeloid-derived suppressor cell expansion during tumor progression.

Dr. Lyden's laboratory then went on to show that growth factors secreted by the primary tumor prime certain tissues for tumor cell engraftment (Nature 2005, 438:820-827). His laboratory defined the concept of the "pre-metastatic niche", showing that in response to tumor-secreted factors, tumor-associated cells such as hematopoietic progenitor cells are recruited to future metastatic niches creating an environment that is conducive for tumor cell adhesion and invasion. At the pre-metastatic niche, newly recruited myeloid cells collaborate with other cells types residing in the tissue parenchyma. Together, these cells provide a platform of chemokines (such as S100 family members), growth factors, matrix-degrading enzymes (MMP9) and adhesion molecules (fibronectin and laminin), thereby accelerating assembly of the metastatic lesion. This model suggests that it may be beneficial for systemic therapies targeted to the metastatic microenvironment to be used early, perhaps even as an adjunct to the initial treatment of the primary tumor (Nature Reviews Cancer 2009, 9:285-293; Nature Reviews Cancer 2015, In Press). Finally, there is the implication that treatments may need to be tailored to each stage of metastatic progression: pre-metastatic, micrometastatic and macrometastatic as well as to specific metastatic niches (lung, liver, brain, bone marrow). Dr. Lyden's team investigation of tumor-secreted factors that mediate the crosstalk between tumors and cells in the remote metastatic microenvironment has led to his recent discovery that tumor-secreted microvesicles, known as exosomes, initiate pre-metastatic niche formation by educating bone marrow progenitor cells towards a pro-angiogenic phenotype, thus supporting a metastatic phenotype (Nature Medicine 2012, 18[6]: 883-894).

Dr. Lyden's laboratory has focused much of its recent activity on understanding the role of tumor-secreted exosomes in cancer metastasis (Nature Medicine 2012, 18[6]: 883-894; Costa da Silva B et al, Nature Cell Biology, In Press). The lab's current studies are focused on the molecular pathways activated by tumor exosome uptake at the metastatic site and identifying potential therapeutic targets to thwart metastasis. His team has made significant contributions to the identification of the role of exosomes in melanoma, pancreatic and breast cancer metastasis. He has isolated high quality exosome preparations from a large number of cancer cell lines as well as cancer patients and determined their functional role in metastasis. Collaborating closely with Drs. Yibin Kang and Ben Garcia, as well as Henrik Molina of the Rockefeller University Proteomics Resource Center, he has developed methods for exosome proteomics, which led to the identification of several biomarkers with diagnostic and prognostic value in melanoma (Peinado et al, Nature Medicine 2012, 18[6]:883-894), pancreatic cancer (Costa da Silva B et al, Nature Cell Biology, In Press) and breast cancer patients. Importantly, his team has demonstrated that tumor-derived exosomes not only contain RNAs and proteins, but that their cargo includes double-stranded DNA, representing the entire genome of the tumor cell of origin (Thakur et al, Cell Research 2014, 24(6):766-9). These findings have important implications, as double-stranded DNA shielded in the exosomes could potentially serve as a stable and reliable prognostic marker in monitoring response to therapy and predicting the progression of melanoma in patients at earlier stages of the disease.